The present invention concerns benzothieno[3,2-c]pyridine derivatives having central xcex12-adrenoceptor antagonist activity. It further relates to their preparation, compositions comprising them and their use as a medicine.
Central xcex12-adrenoceptor antagonists are known to increase noradrenaline release by blocking presynaptic xcex12-receptors which exert an inhibiting control over the release of the neurotransmitter. By increasing the noradrenaline concentrations, xcex12-antagonists can be used clinically for the treatment or prophylaxis of depression, cognitive disturbances, Parkinson""s disease, diabetes mellitus, sexual dysfunction and impotence, elevated intraocular pressure, and diseases related to disturbed enterokinesia, since all these conditions are associated with a deficiency of noradrenaline in the central or peripheral nervous system.
The compounds of the present invention are novel and have a specific and selective binding affinity for the different known subtypes of the xcex12-adrenoceptors, i.e. the xcex12A, xcex12B and xcex12C-adrenoceptor.
The present invention concerns the compounds of formula 
the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein:
each R1 is independently hydrogen, halogen, C1-6alkyl, nitro, hydroxy or C1-4alkyloxy;
Alk is C1-6alkanediyl;
n is 1 or 2;
p is 0, 1 or 2;
D is 1- or 2-benzimidazolyl, 2(3H)benzoxazolone-3-yl or a radical of formula 
wherein
each X independently represents O, S or NR12;
R2 is hydrogen, C1-6alkyl, aryl or arylC1-6alkyl;
R3 is hydrogen, C1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino or mono- or di(C1-6alkyl)amino;
R4, R5, R6, R7, R8, R10, R11 and R12 each independently are hydrogen or C1-6alkyl;
R9 is hydrogen, C1-6alkyl or aryl; or
R3 and R4 taken together may form a bivalent radical xe2x80x94R3xe2x80x94R4xe2x80x94 of formula 
wherein one or two hydrogen atoms of said radicals (a-1) to (a-5) each independently may be replaced by halo, C1-6alkyl, arylC1-6alkyl, trifluoromethyl, amino, hydroxy, C1-6alkyloxy or C1-10alkylcarbonyloxy; or where possible, two geminal hydrogen atoms may be replaced by C1-6alkylidene or arylC1-6alkylidene; or 
wherein one or where possible two or three hydrogen atoms in said radicals (a-6) to (a-14) each independently may be replaced by C1-6alkyl or aryl; and aryl is phenyl or phenyl substituted with one, two or three substituents selected from halo, hydroxy, nitro, cyano, trifluoromethyl, C1-6alkyl, C1-6alkyloxy, C1-6alkylthio, mercapto, amino, mono- and di(C1-6alkyl)amino, carboxyl, C1-6alkyloxycarbonyl and C1-6alkylcarbonyl.
As used in the foregoing definitions the term halogen is generic to fluoro, chloro, bromo and iodo. The term C1-6alkyl defines straight and branched saturated hydro-carbons, having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, pentyl, hexyl and the like. The term C1-10alkyl is meant to include C1-6alkyl radicals and the higher homologues thereof having 7 to 10 carbon atoms such as, for example, heptyl, octyl, nonyl, decyl and the like. The term C1-6alkanediyl defines bivalent straight or branch chained alkanediyl radicals having from 1 to 6 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the like; the term C1-6alkylidene defines bivalent straight or branch chained alkylidene radicals having from 1 to 6 carbon atoms such as, for example, methylene, ethylidene, 1-propylidene, 1-butylidene, 1-pentylidene, 1-hexylidene and the like.
The addition salts as mentioned herein are meant to comprise the therapeutically active addition salt forms which the compounds of formula (I) are able to form with appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
The pharmaceutically acceptable addition salts as mentioned hereinabove are also meant to comprise the therapeutically active non-toxic base, in particular, a metal or amine addition salt forms which the compounds of formula (I) are able to form. Said salts can conveniently be obtained by treating the compounds of formula (I) containing acidic hydrogen atoms with appropriate organic and inorganic bases such as, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
Conversely said salt forms can be converted by treatment with an appropriate base or acid into the free acid or base form.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) are able to form and said solvates are meant to be included within the scope of the present invention. Examples of such solvates are, e.g. the hydrates, alcoholates and the like.
The N-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
The term stereochemically isomeric forms as used herein defines all the possible isomeric forms in which the compounds of formula (I) may occur. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure.
Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
Whenever used hereinafter, the term compounds of formula (I) is meant to include also the N-oxide forms, the pharmaceutically acceptable addition salts and all stereoisomeric forms.
Suitably, aryl is phenyl or phenyl substituted halo or C1-6alkyl.
A special group of compounds are those compounds of formula (I) wherein p is 0.
An interesting group of compounds are those compounds of formula (I) wherein n is 1 and R1 is hydrogen, chloro, fluoro, methyl, methoxy or nitro, in particular R1 is hydrogen or chloro; or, wherein n is 2 and both R1 are methoxy. Preferred positions for R1 are position 7 and 8 as depicted below. 
Another interesting group of compounds are those compounds of formula (I) wherein Alk is methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl or 1,5-pentanediyl, in particular 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, more in particular 1,2-ethanediyl.
Still another interesting group of compounds are those compounds of formula (I) wherein D is a radical of formula (a), (b), (c), (d) or (f).
Particular compounds are those compounds of formula (I) wherein D is a radical of formula (a) wherein R2 is C1-6alkyl, aryl or arylC1-6alkyl, and R3 and R4 form a bivalent radical of formula xe2x80x94R3xe2x80x94R4xe2x80x94, and suitably xe2x80x94R3xe2x80x94R4xe2x80x94 is a radical of formula (a-5) or (a-8); or D is a radical of formula (b) wherein R5 and R6 are C1-6alkyl; or D is a radical of formula (c) wherein R7 is hydrogen; or D is a radical of formula (d) wherein R8 is hydrogen; or D is a radical of formula (f) wherein R10 is hydrogen and X is O or S, in particular S.
Preferred compounds are those compounds of formula (I) wherein n is 1 and R1 is hydrogen or chloro, p is 0, Alk is 1,2-ethanediyl and D is a radical of formula (a), (b), (c), (d) or (f).
Most preferred compounds are the compounds depicted below or their N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof: 
The compounds of formula (I) can generally be prepared by N-alkylating a benzo-thieno[3,2-c]pyridine derivative of formula (II) with an alkylating reagent of formula (III) following the procedure described in EP-A-0,037,265, EP-A-0,070,053, EP-A-0,196,132 and in EP-A-0,378,255. Conveniently, both intermediates are reacted in a suitable solvent such as, for example, methylisobutyl keton, in the presence of a base such as, for example, sodium carbonate, and optionally in the presence of a catalyst such as, for example, potassium iodide. 
In intermediate (III), W1 represents an appropriate reactive leaving group such as, for example, halo, e.g. chloro, bromo or iodo; sulfonyloxy, e.g. methanesulfonyloxy, 4-methylbenzenesulfonyloxy.
In this and the following reactions, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as extraction, crystallization, trituration and chromatography.
The compounds of formula (I) wherein D is a radical of formula (e), being represented by formula (I-e), may be prepared by deprotecting a N-protected intermediate of formula (IV) wherein P is a protective group such as, for example, a C1-4alkyloxy-carbonyl group, and subsequently N-acylating the resulting intermediate with an acyl derivative of formula (V) wherein W2 is an appropriate reactive leaving group such as, for example, a halogen. The reaction may be performed in a suitable solvent such as, for example, chloroform, methylisobutyl keton or an alcohol, in the presence of a base such as, for example, sodium carbonate. 
The compounds of formula (I) wherein D is a radical of formula (f), being represented by formula (I-f), can be prepared by N-alkylating an amine of formula (VI) with an intermediate of formula (VII) wherein W3 is an appropriate reactive leaving group such as, for example, a halogen. 
The compounds of formula (I) may be converted into each other following art-known functional group transformation reactions.
The compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
A number of intermediates and starting materials are commercially available or are known compounds which may be prepared according to art-known methodologies.
For example, some of the intermediates of formula (III) and their preparations are described in EP-A-0,037,265, EP-A-0,070,053, EP-A-0,196,132 and in EP-A-0,378,255.
Intermediates of formula (II) wherein X is S can be prepared analogous to the procedure described in Capps et al. (J. Am. Chem. Soc., 1953, p. 697) or U.S. Pat. No. 3,752,820.
A particular synthesis route for the preparation of intermediates of formula (II) is depicted in scheme 1. 
Step a can be performed analogous to the procedure described in Tetrahedron (1981), 37, p 979-982. Benzofurans resulting from step c have been used as intermediates in U.S. Pat. No. 4,210,655. The further reaction steps are analogous to the reaction procedures described in U.S. Pat. No.3,752,820.
Alternatively, intermediates of formula (II) can be prepared using the reaction steps depicted in scheme 2. 
Step a can be performed analogous to the procedure described in Heterocycles (1994), 39(1), p. 371-380. Step b can be performed analogous to the procedure described in J. Med. Chem. (1986), 29(9), p. 1643-1650. Further reaction steps can be performed analogous to the ones described in J. Heterocycl. Chem. (1979), 16, p. 1321.
Some of the compounds of formula (I) and some of the intermediates in the present invention contain at least one asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers.
Pure stereochemically isomeric forms of the compounds of formula (I) may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically. The pure and mixed stereochemically isomeric forms of the compounds of formula (I) are intended to be embraced within the scope of the present invention.
The compounds of formula (I), the N-oxides, the pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, block the presynaptic xcex12-receptors on central noradrenergic neurons thus increasing the noradrenaline release. Blocking said receptors will suppress or relieve a variety of symptoms associated with a deficiency of noradrenaline in the central or peripheral nervous system. Therapeutic indications for using the present compounds are depression, cognitive disturbances, Parkinson""s disease, diabetes mellitus, sexual dysfunction and impotence and elevated intraocular pressure.
Blocking xcex12 receptors in the central nervous system has also been shown to enhance the release of serotonine which may add to the therapeutic action in depression (Maura et al., 1992, Naunyn-Schmiedeberg""s Arch. Pharmacol., 345 : 410-416).
It has also been shown that blocking xcex12 receptors may induce an increase of extracellular DOPAC (3,4-dihydro-phenylacetic acid) which is a metabolite of dopamine and noradrenaline.
In view of the usefulness of the subject compounds in the treatment of diseases associated with a deficiency of noradrenaline in the central nervous system, in particular depression and Parkinson""s disease, the present invention provides a method of treating warm-blooded animals suffering from such diseases, in particular depression and Parkinson""s disease, said method comprising the systemic administration of an therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable addition salt thereof.
The present compounds are also potentially useful in the treatment of Alzheimer""s disease and dementia as it is known that xcex12-antagonists promote the release of acetylcholine (Tellez et al. 1997, J. Neurochem. 68:778-785).
In general it is contemplated that an effective therapeutic daily amount would be from about 0.01 mg/kg to about 4 mg/kg body weight.
The present invention thus also relates to compounds of formula (I) as defined hereinabove for use as a medicine. Further, the present invention also relates to the use of a compound of formula (I) for the manufacture of a medicament for treating depression or Parkinson""s disease.
Ex vivo as well as in vitro receptor signal-transduction and receptor binding studies can be used to evaluate the xcex12 adrenoceptor antagonism of the present compounds. As indices of central xcex12-adrenoceptor blockade in vivo, the reversal of the loss of righting reflex observed in rats after intravenous injection of xylazine and inhibition of the tremors induced by reserpine in rats can be used.
The compounds of the present invention also have the ability to rapidly penetrate into the central nervous system.
For administration purposes, the subject compounds may be formulated into various pharmaceutical compositions comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound of formula (I). To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in addition salt or in free acid or base form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions containing compounds of formula (I) may be formulated in an oil for prolonged action. Appropriate oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soy bean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment. Addition salts of (I) due to their increased water solubility over the corresponding free base or free acid form, are obviously more suitable in the preparation of aqueous compositions.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.